The complaints of "numb feet" and "burning toes" are common in clinical practice, with a prevalence of approximately 2,400 per 100,000 (2.4 percent) of the population.1 Peripheral neuropathy (PN) refers to a group of disorders (polyneuropathy, single and multiple mononeuropathies, and polyradiculopathy) resulting in altered function and structure of peripheral motor, sensory, and autonomic nerve fibers.

APPROACH TO DIAGNOSIS
Finding the cause of peripheral neuropathy can be accomplished at least 50 percent and up to 75 percent of the time with careful evaluation. Because there are so many etiologies, the key to an efficient approach is being able to recognize certain anatomical patterns in the history, clinical examination, and diagnostic studies. The main causes of neuropathy worldwide include entrapment, Hansen disease, diabetes mellitus, and other systemic disease, inherited disorders, inflammatory demyelination, ischemia, paraneoplastic conditions, deficiency states, and toxins. One approach to assessing these neuropathies is to ask a few basic questions:2

  • What is the anatomical pattern of deficits (distal, proximal or one body region)?
  • Is there modality specificity (motor, sensory, or autonomic)?
  • What is the temporal profile (acute or chronic)?
  • What is the severity (mild, moderate, or severe)?
  • What is the pathology on whole nerve biopsy: axonal, demyelinating, or mixed? (Even though this testing rarely is needed anymore.)

HISTORY
A careful history helps to establish other discernable features. "Funny-shaped" feet, claw toes, or a memorable relative with chronic foot problems are all important clues to inherited neuropathy. Not being able to rise from a chair suggests proximal motor involvement, and being unable to sleep soundly at night due to "burning feet" alerts the clinician to possible distal sensory nerve dysfunction.

Consider the temporal profile of the neuropathy. Elicit the onset, duration and evolution of symptoms. An acute pattern (less than four weeks) suggests vasculitis or the Guillain-BarrŽ syndrome (GBS), while a metabolic event or toxic exposure is more commonly subacute (one to three months) in onset. More typical in most PN is a slow or insidious progression over months to years (diabetic polyneuropathy, chronic inflammatory demyelinating polyradiculopathy, hereditary neuropathy). A history of relapsing and remitting symptoms suggests CIDP or other immune related neuropathy, or much less often porphyria.

Seek characterization of the symptoms. This will aid the clinician in the classification of the anatomical pattern of the neuropathy and in determination of the specific nerve fiber modalities involved. Time spent listening to the individual's descriptive features is often undervalued. Identification of the "positive" (tingling, "pins and needles") and "negative" (dead numbness, loss of feeling, "walking on blocks of wood") sensory symptoms conveys information as to the etiology. "Positive" symptoms are suggestive of acquired causes, while "negative" are more commonly linked to inherited disorders. The patient who is oblivious to his/her symptoms suggests a hereditary neuropathy.

Identify whether the symptoms are described as symmetric and clarify if they are predominantly proximal or distal. Metabolic and toxin-associated neuropathies typically present as a distal symmetric or dying back process. Proximal sensory neuropathies are rare and include occult malignancy or more rarely porphyria. Neuropathies known for being painful include those associated with diabetes mellitus, impaired glucose tolerance, metabolic syndrome, vasculitis, Guillain-BarrŽ syndrome, amyloidosis, toxins, and Fabry disease. A primary complaint of painless dysequilibrium suggests a loss of large myelinated fibers.3

Neuropathy patients seldom volunteer focal symptoms of motor weakness, but they often report the inability to ascend stairs, the embarrassment of tripping easily, or the sense that their legs are "tired."

Define the severity of symptoms. The presence of exercise-related pain as a prominent feature suggests ischemic neuropathy.

Consider associations with present or past disease. A variety of systemic, infectious, inflammatory, and malignant diseases as well as toxins are companions of neuropathy. Constitutional symptoms, such as weight loss, malaise, and anorexia, are important diagnostic clues.

Assess for associations with medications or toxins. The natural history of neuropathies associated with toxins is often dose-related, with insidious progression over weeks or months. The counterintuitive "coasting" phenomenon often occurs with symptoms continuing to evolve and worsen up to four to six months after discontinuation of neurotoxic chemotherapy agents.2 Diagnosis begins with a high degree of clinical suspicion during the history, the presence of weakness and sensory loss on physical exam, and electrodiagnostic features of axonal neuropathy.

Decide whether the disorder is likely to be inherited or acquired. Questions uncovering whether family members had high-arched feet, hammer or claw toes, wasting muscles, complained about foot pain, had difficulty walking on heels, used foot braces, or had difficulty rising from a kneeling position are all pertinent in uncovering a hereditary link. After a careful history, the pattern of pathophysiology (metabolic, inflammatory, inherited, toxic or vascular) begins to emerge. The physical examination will then help to confirm this pattern, define the severity, and clarify additional unrecognized features that may further aid in the diagnosis.

Peripheral neuropathies often have a distinguishing pattern of findings on the clinical examination.1-6 Unilateral motor and sensory signs are associated with disease of a single root (monoradiculopathy), or brachial plexus or lumbar plexopathy. Multiple mononeuropathies (or mononeuropathy multiplex) denotes sequential damage to multiple noncontiguous nerves. Distal sensorimotor polyneuropathy is characterized by symmetrical, distal motor and sensory deficits with a graded increase in severity distally and distal reduction of reflexes.5 The physical examination helps to establish the anatomical pattern, which is narrowed to specific modalities (motor, sensory, autonomic). To recognize these diagnostic features is not easy and often requires diligence coupled with the experience of seeing them over and over again in several patients.

Do the symptoms and exam suggest a focal pattern or multiple nerves involved? Mononeuro-pathy involves a focal lesion of a single peripheral nerve. Carpal tunnel syndrome is the most common entrapment disorder of a single nerve. The most vulnerable nerves to entrapment are the median, ulnar and fibular (peroneal) nerves. Multiple mononeuropathies (previously called mononeuropathy multiplex (MM)) is the involvement of noncontiguous peripheral nerves either simultaneously or sequentially. The pattern of involvement can progress in a random, multifocal fashion, even to a point of summation resulting in confluent and symmetric deficits mimicking a distal symmetric polyneuropathy (this can be tricky).

The simultaneous diffuse involvement of all peripheral nerves is known as polyneuropathy. Polyneuropathies are typically bilateral and fairly symmetric with a distal-to–proximal pattern of sensory loss and/or motor weakness. Distal symmetrical polyneuropathy is the most common variety of polyneuropathy. The sensory deficits create a "stocking-glove" pattern. This pattern is associated with several etiologies (See Table 2).1-7 Of this prototype, diabetes mellitus is the most common polyneuropathy in the developed world.1 The most commonly seen subtype of painful polyneuropathy is a special form known as small-fiber sensory neuropathy. The patient presents with complaints of a chronic, slowly evolving loss of sensation in the distal extremities associated with or without pain. Pain is often the most disabling feature, even though progression to non-ambulatory disability is very rare.

Peripheral nerves and nerve roots of spinal nerves are the anatomical sites involved and are marked by demyelination or axon degeneration. Polyradiculoneuropathy tends to follow an acute temporal course with a variety of causes (Table 3).2 They can, however, evolve in a more chronic pattern with the same underlying pathophysiology. Polyradiculoneuropathies are length dependent with moderate to severe weakness of proximal and distal muscles with sensory loss in proximal and distal areas.

CATEGORIZING BY MODALITY
Neuropathy can be further categorized according to the modality (nerve fiber type) that is principally involved (motor, sensory, autonomic). Electromyography (EMG) is a valuable tool in providing objective evidence to support the diagnosis of PN by making deductions about pathologic alterations of fibers (axonal degeneration or demyelination) as well as distribution, type and severity of deficits, and the duration and course of the neuropathy. The complementary needle exam determines whether abnormal conduction results are due to muscle or nerve disease. Both the nerve conduction study and needle examination are important elements to establishing the anatomic-pathologic pattern for the diagnosis of PN. The EMG should precede testing for common causes of PN.2

Quantitative sensory testing—although dependent on subjective responses from the patient—is useful to detect or confirm sensory loss and to identify the modality and class of fibers affected. This investigation can be helpful in identifying small fiber neuropathy.2

Autonomic testing is beneficial in the categorization of various types of sympathetic and parasympathetic dysfunction and may help to localize the disorder as either central or peripheral in origin. An additional test available in a few academic centers is the thermoregulatory sweating test, which may reveal quite striking neurologic impairment not readily apparent by clinical or other diagnostic tests.2

Biopsies. Before committing a patient to the prospect of long-term corticosteroid treatment, it is important to document a pathological diagnosis of necrotizing vasculitis. The sural nerve biopsy may provide a specific diagnosis in amyloidosis, Hansen disease, sarcoidosis, tumor infiltration and hereditary neuropathy with predisposition to pressure palsies.2 A skin punch biopsy is effective in documenting the density of epidermal nerve fibers and is considered a sensitive indicator of small fiber neuropathy.10

Diagnostic radiography, myelography, CT and MRI may provide additional information for anatomic localization (lesions in roots, ganglia or nerves or a variety of structures impinging on nerves).2

Hematological, Genetic and Biological Testing are not employed to diagnose Polyneuropathy. Rather, laboratory tests are routinely utilized in patients with the confirmed diagnosis of polyneuropathy as a screening for specific etiologies. The majority of studies indicate that a few screening laboratory tests are helpful (See Table 4). A second group of studies can be ordered in selective cases when uncommon etiologies are considered.8 It is probably a mistake and certainly a poor use of resources to order a comprehensive slate of diagnostic tests on every neuropathy patient.

The role of genetic testing should be considered for accurate diagnosis and classification of hereditary neuropathies. The majority of genetically determined polyneuropathies are variants of Charcot-Marie-Tooth disease. Specific testing is available for an increasing number of these neuropathies on a commercial basis.

Lumbar puncture for spinal fluid analysis is warranted if there is a suspicion for an acquired demyelinating neuropathy (GBS, CIDP) or leptomeningeal malignancy.2

MANAGEMENT
The most successful treatment of peripheral neuropathy is correction of the underlying disease. When this is not feasible, symptomatic relief becomes the therapeutic goal by addressing neuropathic pain and gait instability. For patients with painful peripheral neuropathy, regardless of the underlying pathophysiology, the symptomatic approach is the same: relief of pain. Initially, simple analgesics (acetaminophen and nonsteroidal anti-inflammatory drugs) may provide relief. Topical anesthetic agents have the advantage of providing some relief with minimum side effects when a small patch of skin is affected. Four broad categories of drugs are available to the clinician including serotonin-norepinephrine reuptake inhibitors, tricyclic analgesics, anticonvulsants, and opiates. If monotherapy fails after all single agents have received an adequate trial, patients may respond to combination therapy. Narcotic analgesic treatment, while considered by some as a first-tier treatment agent based on its effectiveness in pain relief, is still reserved for refractory treatment by most authorities. The clinician's choice must include consideration of adverse effects, individual patient factors, comorbidities and cost.

Treating concomitant sleep disorders, depression, and social withdrawal frequently adds to the quality-of-life for patients with chronic neuropathic pain syndromes. Studies of patients with diabetic neuropathic pain revealed greater impairment on measures of emotional reactions, energy, pain, physical mobility, sleep and interference with enjoyment of life. No agent has been shown to be effective for all patients, and it is worth noting that symptoms of numbness and tingling without pain will not benefit from use of medications. Gait aids and training are important to aid mobility and reduce the risks of falls. Therapies such as acupuncture and transcutaneous electrical nerve stimulations sometimes show benefit.11

For immune-mediated peripheral neuropathies (acute inflammatory demyelinating polyneuropathy (AIDP), CIDP, or vasculitis) a wide range of immunosuppressive therapies are available; some are proven, others are under study. Autonomic neuropathies can be managed first with lifestyle changes (increased salt intake, compression stockings or belt, elevation of the head of the bed, and intake of frequent small versus large meals). Additional medications for therapy include fludorcortisone, midodrine and pyridostigmine.2

For those patients with hereditary neuropathy, addressing life issues such as loss of independence, emotional pain, and stress over the guilt of passing along a gene mutation to their children and fear of progressive disability can benefit by discussion with an experienced genetic counselor.2 Addressing disease modification, neuropathic pain, disabilities, psychosocial and emotional issues specific to the individual at different life and disease stages usually requires a multi-disciplinary team approach to provide appropriate management for the older adult with peripheral neuropathy.